A majority of people with diabetes die of cardiovascular disease caused by atherosclerosis. Both hyperglycemia and hypertriglyceridemia are believed to contribute to the increased cardiovascular disease. No animal model to date has been able to distinguish between the contributions of hyperglycemia and hypertriglyceridemia to plaque progression. Accumulation of macrophages in advanced plaques is likely to lead to plaque progression. We hypothesize that the increased fatty acid load associated with hypertriglyceridemia in diabetes causes plaque progression by stimulating macrophage accumulation and secretion of proteases. In this competitive renewal, we propose to address the following questions: 1) Is diabetes-induced hypertriglyceridemia necessary for progression of pre-existing lesions? We have developed a mouse model of diabetes-accelerated atherosclerosis that can be used to separate effects of hyperglycemia and hypertriglyceridemia on plaque progression. The effect of diabetes-induced hypertriglyceridemia on pre-existing plaques will be studied. 2) Does lowering of hypertriglyceridemia in the presence of hyperglycemia prevent diabetes-accelerated plaque progression? We propose to use a helper-dependent adenoviral vector to overexpress the VLDL receptor in livers of diabetic mice, thereby normalizing hypertriglyceridemia. 3) Does increased fatty acid load lead to increased macrophage accumulation and protease secretion ex vivo? We propose to expose isolated macrophages to increased or decreased fatty acid load. 4) Is increased fatty acid load in macrophages necessary and sufficient for plaque progression? We propose use a macrophage-selective retroviral vector to overexpress acyl-CoA synthetase 1 (Acsll) in macrophages, and also to generate a mouse with macrophage-targeted deletion on Acsll. The effect on progression of pre-existing lesions will be investigated. We expect that these studies will significantly increase our understanding of the role of hypertriglyceridemia in plaque progression in diabetes, and may provide the basic information necessary for development of drugs or gene therapies that can prevent or slow down cardiovascular complications of diabetes.